Indole-type inhibitors of p38 kinase

ABSTRACT

Compounds that inhibit p38-α kinase are those wherein a bicyclic aromatic system is coupled through a saturated ring to an aryl group.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 09/989,991 filed 20Nov. 2001 and now allowed which claims priority under 35 U.S.C. §119(e)from U.S. Ser. No. 60/252,163 filed 20 Nov. 2000.

TECHNICAL FIELD

The invention relates to treating various disorders associated withenhanced activity of kinase p38-α. More specifically, it concernsindole-type derivatives useful in these methods.

BACKGROUND ART

A large number of chronic and acute conditions have been recognized tobe associated with perturbation of the inflammatory response. A largenumber of cytokines participate in this response, including IL-1, IL-6,IL-8 and TNF. It appears that the activity of these cytokines in theregulation of inflammation rely at least in part on the activation of anenzyme on the cell signaling pathway, a member of the MAP kinase familygenerally known as p38 and alternatively known as CSBP and RK. Thiskinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with lipopolysaccharides or withproinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors ofthe kinase activity of p38 are useful anti-inflammatory agents.

Eye diseases associated with a fibroproliferative condition includeretinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery.

PCT applications WO 98/06715, WO 98/07425, and WO 96/40143, all of whichare incorporated herein by reference, describe the relationship of p38kinase inhibitors with various disease states. As mentioned in theseapplications, inhibitors of p38 kinase are useful in treating a varietyof diseases associated with chronic inflammation. These applicationslist rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, sepsis, septic shock,endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma,adult respiratory distress syndrome, stroke, reperfusion injury, CNSinjuries such as neural trauma and ischemia, psoriasis, restenosis,cerebral malaria, chronic pulmonary inflammatory disease, silicosis,pulmonary sarcosis, bone resorption diseases such as osteoporosis,graft-versus-host reaction, Crohn's Disease, ulcerative colitisincluding inflammatory bowel disease (IBD) and pyresis.

The above-referenced PCT applications disclose compounds which are p38kinase inhibitors said to be useful in treating these disease states.These compounds are either imidazoles or are indoles substituted at the3- or 4-position with a piperazine ring linked through a carboxamidelinkage. Additional compounds which are conjugates of piperazines withindoles are described as insecticides in WO 97/26252, also incorporatedherein by reference.

Certain aroyl/phenyl-substituted piperazines and piperidines whichinhibit p38-α kinase are described in PCT publication WO 00/12074published 9 Mar. 2000. In addition, indolyl substituted piperidines andpiperazines which inhibit this enzyme are described in PCT publicationNo. WO 99/61426 published 2 Dec. 1999. Carbolene derivatives ofpiperidine and piperazine as p38-α inhibitors are described inPCT/US00/07934 filed 24 Mar. 2000.

None of the foregoing patents describes the indole derivatives describedherein which specifically inhibit p38-α.

DISCLOSURE OF THE INVENTION

The invention is directed to methods and compounds useful in treatingconditions that are characterized by enhanced p38-α activity. Theseconditions include inflammation, proliferative diseases, and certaincardiovascular disorders as well as Alzheimer's disease as furtherdescribed below.

Compounds of the invention inhibit p38 kinase, the α-isoform inparticular, and are thus useful in treating diseases mediated by theseactivities. The compounds of the invention are of the formula

-   -   and the pharmaceutically acceptable salts thereof, or a        pharmaceutical composition thereof, wherein:    -   Ar is an aryl group substituted with 0-5 noninterfering        substituents, wherein two adjacent noninterfering substituents        can form a fused aromatic or nonaromatic ring;    -   L¹ and L² are linkers;    -   X is an aliphatic monocyclic or aliphatic polycyclic moiety        optionally comprising one or more hetero ring atoms wherein the        cyclic moiety may be optionally substituted with one or more        noninterfering substituents and where said optional substituents        may constitute a ring fused to X;    -   n is 0-3;    -   each R¹ is hydrogen or a noninterfering substituent;        represents a single or double bond;    -   one Z² is CA or CR²A; the other Z² is CR³, CR³ ₂, NR⁴ or N; and        each R², R³ and R⁴ is independently hydrogen or a noninterfering        substituent;    -   Z³ is NR⁵ or O; where R⁵ is hydrogen or a noninterfering        substituent;    -   A is -W_(i)-COX_(j)Y, where Y is COR⁶ or an isostere thereof,        each of W and X is a spacer of 2-6 Å; each of i and j is        independently 0 or 1; and R⁶ is a noninterfering substituent;    -   and wherein the smallest number of covalent bonds in the        compound separating the atom of Ar linked to L² and the atom of        the α ring linked to L¹ is at least 5, each said bond having a        bond length of 1.2 to 2.0 angstroms; and/or the distance in        space between the atom of Ar linked to L² and the atom of the a        ring linked to L¹ is 4.5-24 angstroms.    -   and with the proviso that the portion of the compound        represented by L²-X-L¹ is not:    -   where L² and L¹ are linkers; Z^(a) is CR or N wherein R is        hydrogen or a noninterfering substituent; each R^(a) is        independently a noninterfering substituent; and each of 1 and k        is 0-3; and m is 0-4.

The invention is further directed to methods of treating inflammation orproliferative conditions using these compounds. The invention is alsodirected to treating conditions associated with cardiac failure andAlzheimer's disease using the invention compounds.

MODES OF CARRYING OUT THE INVENTION

The compounds of formula (1) are useful in treating conditions which arecharacterized by overactivity of p38 kinase, in particular theα-isoform. Conditions “characterized by enhanced p38-α activity” includethose where this enzyme is present in increased amount or wherein theenzyme has been modified to increase its inherent activity, or both.Thus, “enhanced activity” refers to any condition wherein theeffectiveness of these proteins is undesirably high, regardless of thecause.

The compounds of the invention are useful in conditions where p38-αkinase shows enhanced activity. These conditions are those in whichfibrosis and organ sclerosis are caused by, or accompanied by,inflammation, oxidation injury, hypoxia, altered temperature orextracellular osmolarity, conditions causing cellular stress, apoptosisor necrosis. These conditions include ischemia-reperfusion injury,congestive heart failure, progressive pulmonary and bronchial fibrosis,hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis,interstitial renal fibrosis, chronic scarring diseases of the eyes,bladder and reproductive tract, bone marrow dysplasia, chronicinfectious or autoimmune states, spinal chord injury and traumatic orsurgical wounds. These conditions, of course, would be benefited bycompounds which inhibit p38-α. Methods of treatment with the compoundsof the invention are further discussed below.

The compounds useful in the invention are derivatives of indole-typecompounds containing a mandatory substituent, A, at a positioncorresponding to the 2- or 3-position of indole. In general, anindole-type nucleus is preferred, although alternatives within the scopeof the invention are also illustrated below.

In the description above, certain positions of the molecule aredescribed as permitting “noninterfering substituents.” This terminologyis used because the substituents in these positions generally speakingare not relevant to the essential activity of the molecule taken as awhole. A wide variety of substituents can be employed in thesepositions, and it is well within ordinary skill to determine whether anyparticular arbitrary substituent is or is not “noninterfering.”

As used herein, a “noninterfering substituent” is a substituent whichleaves the ability of the compound of formula (1) to inhibit p38-αactivity qualitatively intact. Thus, the substituent may alter thedegree of inhibition of p38-α. However, as long as the compound offormula (1) retains the ability to inhibit p38-α activity, thesubstituent will be classified as “noninterfering.” A number of assaysfor determining the ability of any compound to inhibit p38-α activityare available in the art. A whole blood assay for this evaluation isillustrated below. The gene for p38-α has been cloned and the proteincan be prepared recombinantly and its activity assessed, including anassessment of the ability of an arbitrarily chosen compound to interferewith this activity. The essential features of the molecule are tightlydefined. The positions which are occupied by “noninterferingsubstituents” can be substituted by conventional organic moieties as isunderstood in the art. It is irrelevant to the present invention to testthe outer limits of such substitutions. The essential features of thecompounds are those set forth with particularity herein.

In addition, L¹ and L² are described herein as linkers. The nature ofsuch linkers is less important than the distance they impart between theportions of the molecule. Typical linkers include alkylene, i.e.(CH₂)_(n)—R; alkenylene—i.e., an alkylene moiety which contains a doublebond, including a double bond at one terminus. Other suitable linkersinclude, for example, substituted alkylenes or alkenylenes, carbonylmoieties, and the like.

As used herein, “hydrocarbyl residue” refers to a residue which containsonly carbon and hydrogen. The residue may be aliphatic or aromatic,straight-chain, cyclic, branched, saturated or unsaturated. Thehydrocarbyl residue, when so stated however, may contain heteroatomsover and above the carbon and hydrogen members of the substituentresidue. Thus, when specifically noted as containing such heteroatoms,the hydrocarbyl residue may also contain carbonyl groups, amino groups,hydroxyl groups and the like, or contain heteroatoms within the“backbone” of the hydrocarbyl residue.

As used herein, “inorganic residue” refers to a residue that does notcontain carbon. Examples include, but are not limited to, halo, hydroxy,NO₂ or NH₂.

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the like. Typically, the alkyl, alkenyl andalkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl oralkynyl). Preferably they contain 1-6C (alkyl) or 2-6C (alkenyl oralkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are similarlydefined but may contain 1-2 O, S or N heteroatoms or combinationsthereof within the backbone residue.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl,alkynyl and the related heteroforms which are coupled to an additionalresidue through a carbonyl group.

“Aromatic” moiety refers to a monocyclic or fused bicyclic moiety suchas phenyl or naphthyl; “heteroaromatic” also refers to monocyclic orfused bicyclic ring systems containing one or more heteroatoms selectedfrom O, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings as well as 6-membered rings. Thus, typical aromaticsystems include pyridyl, pyrimidyl, indolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like.Any monocyclic or fused ring bicyclic system which has thecharacteristics of aromaticity in terms of electron distributionthroughout the ring system is included in this definition. Typically,the ring systems contain 5-12 ring member atoms.

Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety.

When the compounds of Formula 1 contain one or more chiral centers, theinvention includes optically pure forms as well as mixtures ofstereoisomers or enantiomers.

With respect to the portion of the compound between the Ar and the ringα, linkers L² and L¹, in combination with the moiety —X—, provide forseparation of the atom of Ar bonded to L² from the atom of the ring abonded to L¹ by a defined minimum number of covalent bond distancescounted end-to-end through the compound, as opposed to a measurement oflinear distance through space. More particularly, the smallest number ofbonds counted end-to-end in the compound separating the atom of Arbonded to L² from the atom of the ring a bonded to L¹ is at least 5, andpreferably from 6 to 12, wherein the length of each of such bonds is 1.2to 2.0 angstroms. In terms of a linear distance through space, thelinear distance measured through space from the atom of Ar bonded to L²to the atom of the ring a bonded to L¹ is a distance of 4.5-24 Å,preferably 6-20 Å, and more preferably 7.5-10 Å.

Typical, but nonlimiting, embodiments of L¹ and L² are CO and isosteresthereof, or optionally substituted isosteres, or longer chain forms. L²,in particular, may be alkylene or alkenylene optionally substituted withnoninterfering substituents or L¹ or L² may be or may include aheteroatom such as N, S or O. Such substituents include, but are limitedto, a moiety selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂,SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR,alkyl-COOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂,wherein each R is independently H, alkyl, alkenyl or aryl or heteroformsthereof, and wherein two substituents on L² can be joined to form anon-aromatic saturated or unsaturated ring that includes 0-3 heteroatomswhich are O, S and/or N and which contains 3 to 8 members or said twosubstituents can be joined to form a carbonyl moiety or an oxime,oximeether, oximeester or ketal of said carbonyl moiety. Furtherexamples of L¹ and L² include —CH₂—NH—CO— and —CH₂—NH—CO—.

Isosteres of CO and CH₂, include SO, SO₂, or CHOH. CO and CH₂ arepreferred.

Thus, L is substituted with 0-2 substituents. Where appropriate, twooptional substituents on L² can be joined to form a non-aromaticsaturated or unsaturated hydrocarbyl ring that includes 0-3 heteroatomssuch as O, S and/or N and which contains 3 to 8 members. Two optionalsubstituents on L² can be joined to form a carbonyl moiety which can besubsequently converted to an oxime, an oximeether, an oximeester, or aketal.

Ar is aryl, heteroaryl, including 6-5 fused heteroaryl, cycloaliphaticor cycloheteroaliphatic that can be optionally substituted. Ar ispreferably optionally substituted phenyl.

Each substituent on Ar is independently a hydrocarbyl residue (1-20C)containing 0-5 heteroatoms selected from O, S and N, or is an inorganicresidue. Preferred substituents include those selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl,heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl,NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR,OCONR₂, RCO, COOR, alkyl-COOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃,R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or arylor heteroforms thereof, and wherein two of said optional substituents onadjacent positions can be joined to form a fused, optionally substitutedaromatic or nonaromatic, saturated or unsaturated ring which contains3-8 members. More preferred substituents include halo, alkyl (1-4C) andmore preferably, fluoro, chloro and methyl. These substituents mayoccupy all available positions of the aryl ring of Ar, preferably 1-2positions, most preferably one position. These substituents may beoptionally substituted with substituents similar to those listed. Ofcourse some substituents, such as halo, are not further substituted, asknown to one skilled in the art.

Two adjacent substituents on Ar can be joined to form a fused,optionally substituted aromatic or nonaromatic, saturated or unsaturatedring which contains 3-8 members.

Moiety —X— in the compound of formula (I) is an aliphatic monocyclic oraliphatic polycyclic moiety optionally comprising one or more heteroring atoms wherein the cyclic moiety may be optionally substituted withone or more noninterfering substituents and where said optionalsubstituents may constitute a ring fused to X. Moiety —X— includesbridged cyclic moieties. Examples of cyclic moieties that may serve asmoiety X include:

Particular examples of —X— in compound (I) are cyclic moieties such thatthe portion of the compound represented by L²-X-L¹ is selected from thegroup consisting of:

-   -   wherein, in each of structures (I) to (IV):    -   one or more of the ring carbon atoms not bound to L² or L¹ may        be optionally replaced with NR⁵, where R⁵ is hydrogen or a        noninterfering substituent; or by CHR² or CR² ₂, where R² is a        noninterfering substituent other than hydrogen; and    -   one or both of the ring carbon atoms bound to L² and L¹ may be        independently replaced with CR or N where R² is independently a        noninterfering substituent other than hydrogen.

The noninterfering substituents R⁵ (i.e. when Z³ is NR⁵) include,without limitation, halo, alkyl, alkoxy, aryl, arylalkyl, aryloxy,heteroaryl, acyl, carboxy, or hydroxy. Preferably, R⁵ is H, alkyl, OR,NR₂, SR or halo, where R is H or alkyl. Additionally, R⁵ can be joinedwith an R¹ substituent (defined below) to form an optionally substitutednon-aromatic saturated or unsaturated hydrocarbyl ring which contains3-8 members and 0-3 heteroatoms such as O, N and/or S. Preferredembodiments include compounds wherein Z¹ is CH or N, and those whereinboth l and k are 1.

Substituents R² and R³ optionally bonded to the moiety —X— representindependently a noninterfering substituent such as a hydrocarbyl residue(1-20C) containing 0-5 heteroatoms selected from O, S and N. PreferablyR² and R³ are independently alkyl, alkoxy, aryl, arylalkyl, aryloxy,heteroalkyl, heteroaryl, heteroarylalkyl, RCO, ═O, acyl, halo, CN, OR,NRCOR, NR, wherein R is H, alkyl (preferably 1-4C), aryl, or heteroforms thereof. Each appropriate substituent is itself unsubstituted orsubstituted with 1-3 substituents. The substituents are preferablyindependently selected from a group that includes alkyl, alkenyl,alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂,SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR,alkyl-COOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂,wherein each R is independently H, alkyl, alkenyl or aryl or heteroformsthereof and two of R² and/or R³ on adjacent positions can be joined toform a fused, optionally substituted aromatic or nonaromatic, saturatedor unsaturated ring which contains 3-8 members, or R² and R³independently are ═O or an oxime, oximeether, oximeester or ketalthereof. Preferred embodiments of R² and R³ comprise alkyl (1-4C)especially two alkyl substituents and carbonyl. Most preferably R² andR³ comprise methyl groups or carbonyl groups. The —X— moiety may bechiral, hence an isolated enantiomer may be preferred.

R¹ represents a noninterfering substituent. Such substituents includehydrocarbyl residues (1-6C) containing 0-2 heteroatoms selected from O,S and/or N and inorganic residues. n is an integer of 0-3, preferably 0or 1. Preferably, the substituents represented by R¹ are independentlyhalo, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR, or NR₂, wherein R is H,alkyl, aryl, or heteroforms thereof. More preferably R¹ substituents areselected from alkyl, alkoxy or halo, and most preferably methoxy,methyl, and chloro. Most preferably, n is 0 and the α ring isunsubstituted, except for L¹ or n is 1 and R³ is halo or methoxy.

In the ring labeled β, Z³ may be NR⁵ or O— i.e., the compounds may berelated to indole or benzofuran. If C³ is NR⁵, preferred embodiments ofR⁵ include H or optionally substituted alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroalkylaryl, or is SOR, SO₂R, RCO, COOR, alkyl-COR,SO₃R, CONR₂, SO₂NR₂, CN, CF₃, NR₂, OR, alkyl-SR, alkyl-SOR, alkyl-SO₂R,alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR₂, or R₃Si, wherein each Ris independently H, alkyl, alkenyl or aryl or heteroforms thereof. Morepreferably, R⁵ is hydrogen or is alkyl (1-4C), preferably methyl or isacyl (1-4C), or is COOR wherein R is H, alkyl, alkenyl of aryl or heteroforms thereof. R⁵ is also preferably a substituted alkyl wherein thepreferred substituents are form ether linkages or contain sulfinic orsulfonic acid moieties. Other preferred substituents include sulfhydrylsubstituted alkyl substituents. Still other preferred substituentsinclude CONR₂ wherein R is defined as above.

It is preferred that the indicated dotted line represents a double bond;however, compounds which contain a saturated β ring are also includedwithin the scope of the invention.

Preferably, the mandatory substituent CA or CR²A is in the 3-position;however, regardless of which position this substituent occupies, theother position is CR³, CR³ ₂, NR⁴ or N. CR³ is preferred. Preferredembodiments of R³ include hydrogen, alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R,OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-COOR, SO₃R,CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R isindependently H, alkyl, alkenyl or aryl or heteroforms thereof and twoof R³ can be joined to form a fused, optionally substituted aromatic ornonaromatic, saturated or unsaturated ring which contains 3-8 members.Most preferably, R³ is H, alkyl, such as methyl, most preferably, thering labeled β contains a double bond and CR³ is CH or C-alkyl. Otherpreferable forms of R³ include H, alkyl, acyl, aryl, arylalkyl,heteroalkyl, heteroaryl, halo, OR, NR₂, SR, NRCOR, alkyl-COOR, RCO,COOR, and CN, wherein each R is independently H, alkyl, or aryl orheteroforms thereof.

While the position not occupied by CA is preferred to include CR³, theposition can also be N or NR⁴. While NR⁴ is less preferred (as in thatcase the ring labeled β would be saturated), if NR⁴ is present,preferred embodiments of R⁴ include H, or alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroalkylaryl, or is SOR, SO₂R, RCO, COOR, alkyl-COR,SO₃R, CONR₂, SO₂NR₂, CN, CF₃, or R₃Si wherein each R is independently H,alkyl, alkenyl or aryl or heteroforms thereof.

Preferably, CR²A or CA occupy position 3- and preferably Z² in thatposition is CA. However, if the β ring is saturated and R² is present,preferred embodiments for R² include H, halo, alkyl, alkenyl and thelike. Preferably R² is a relatively small substituent corresponding, forexample, to H or lower alkyl 1-4C.

A is -W_(i)-COX_(j)Y wherein Y is COR⁶ or an isostere thereof and R⁶ isa noninterfering substituent. Each of W and X is a spacer and may be,for example, optionally substituted alkyl, alkenyl, or alkynyl, each ofi and j is 0 or 1. Preferably, W and X are unsubstituted. Preferably, jis 0 so that the two carbonyl groups are adjacent to each other.Preferably, also, i is 0 so that the proximal CO is adjacent the ring.However, compounds wherein the proximal CO is spaced from the ring canreadily be prepared by selective reduction of an initially glyoxalsubstituted β ring. In the most preferred embodiments of the invention,the α/β ring system is an indole containing CA in position 3- andwherein A is COCR⁶.

The noninterfering substituent represented by R⁶, when R⁶ is other thanH, is a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selectedfrom O, S and/or N or is an inorganic residue. Preferred are embodimentswherein R⁶ is H, or is straight or branched chain alkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl,each optionally substituted with halo, alkyl, heteroalkyl, SR, OR, NR₂,OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, CN, COOR, CONR₂, COR, orR₃Si wherein each R is independently H, alkyl, alkenyl or aryl or theheteroatom-containing forms thereof, or wherein R⁶ is OR, NR₂, SR,NRCONR₂, OCONR₂, or NRSO₂NR₂, wherein each R is independently H, alkyl,alkenyl or aryl or the heteroatom-containing forms thereof, and whereintwo R attached to the same atom may form a 3-8 member ring and whereinsaid ring may further be substituted by alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, each optionallysubstituted with halo, SR, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R,NRSO₂NR₂, OCONR₂, or R₃Si wherein each R is independently H, alkyl,alkenyl or aryl or the heteroatom-containing forms thereof wherein two Rattached to the same atom may form a 3-8 member ring, optionallysubstituted as above defined.

Other preferred embodiments of R⁶ are H, heteroarylalkyl, —NR₂,heteroaryl, —COOR, —NHRNR₂, heteroaryl-COOR, heteroaryloxy, —OR,heteroaryl-NR₂, —NROR and alkyl. Most preferably R⁶ is isopropylpiperazinyl, methyl piperazinyl, dimethylamine, piperazinyl, isobutylcarboxylate, oxycarbonylethyl, morpholinyl, aminoethyldimethylamine,isobutyl carboxylate piperazinyl, oxypiperazinyl, ethylcarboxylatepiperazinyl, methoxy, ethoxy, hydroxy, methyl, amine, aminoethylpyrrolidinyl, aminopropanediol, piperidinyl, pyrrolidinyl-piperidinyl,or methyl piperidinyl.

Isosteres of COR⁶ as represented by Y are defined as follows.

The isosteres have varying lipophilicity and may contribute to enhancedmetabolic stability. Thus, Y, as shown, may be replaced by the isosteresin Table 1. TABLE 1 Acid Isosteres

Names of Groups Chemical Structures Substitution Groups (SG) tetrazole

n/a 1,2,3-triazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂; CF₃; CN; COOMe 1,2,4-triazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂ imidazole

H; SCH₃; COCH₃; Br; SOCH₃; SO₂CH₃; NO₂

Thus, isosteres include tetrazole, 1,2,3-triazole, 1,2,4-triazole andimidazole.

The compounds of formula (1) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compound of formula (1), the compound may also besupplied as a salt with a pharmaceutically acceptable cation.

Synthesis of the Invention Compounds

Copending, commonly-assigned U.S. Ser. No. 09/575,060, incorporatedherein by reference in its entirety, illustrated the following reactionscheme for conversion of a 4-benzyl piperidinyl-indole-5-carboxamide tothe glyoxalic acid compounds of the invention and derivatives thereof:

In the present invention, the piperadinyl moiety is generalized to X informula (I) above where X is an aliphatic monocyclic or aliphaticpolycyclic moiety optionally comprising one or more hetero ring atomswherein the cyclic moiety may be optionally substituted with one or morenoninterfering substituents and where said optional substituents mayconstitute a ring fused to X.

As disclosed commonly assigned in U.S. Ser. No. 09/575,060, the glyoxaltype substituent at position 3 can be generalized to W_(i)COX_(j)Y.

The indole-type moiety may be generalized as:

Methods to synthesize the compounds of the invention are, in general,known in the art. The following general schemes illustrate such methods.

Substituted amino benzoic acid esters such as I can be treated withreagents such as thiomethylacetylaldehyde dimethyl acetal andN-chlorosuccinamide in methylene chloride at low temperature followed bythe treatment with a base such as triethylamine at reflux in methylenechloride, dichloroethane or chloroform to give indoles II, Scheme 1.Treatment with reagents such as Raney-Nickel in an appropriate solventsuch as ethanol, methanol or isopropanol will yield the correspondingindole carboxylic acid ester which when hydrolyzed under base conditionswill give the desired substituted indole carboxylic acid.

Alternatively, substituted amino benzoic acid esters I can be convertedto the ketals IV, Scheme 2, with an appropriate aldehyde underconditions of reductive alkylation with reagents such as sodiumtriacetoxyborohydride in acetic acid in the presence of sodium sulfate.The amines can then be treated with Lewis acids such as aluminumchloride, titanium chloride, BF₃-etherate in dichloromethane ordichloroethane, under reflux to give the corresponding substitutedindole methyl esters, with appropriate substitutions.

Another method could involve the treatment of the substituted aminobenzoic acid esters I with iodine and sodium periodate in an appropriatesolvent such as dimethylformamide, to give the corresponding iodoaniline V, Scheme 3. This can be coupled with an acetylene such astrimethyl silyl acetylene or ethylethenyl ether in the presence of anappropriate catalysts such as palladium and copper and a base such astriethylamine to give the silyl coupled product such as VI. Subsequentcyclization in a solvent such as dimethylformamide and in the presenceof a catalyst such as copper iodide would give the appropriatelysubstituted indoles VII.

Commonly assigned U.S. Ser. No. 09/575,060 disclosed that piperidinemoieties can be obtained by treating an appropriate piperidone such asVIII, Scheme 4, with substituted benzyl phosphonate esters in thepresence of a base such as sodium hydride to give alkenes which can bereduced to the corresponding substituted 4-benzylpiperidine such as IX.The hydrogenations are typically done in the presence of catalyticmetals in solvents such as methanol, ethanol and ethyl acetate. In thepresent invention the piperidone VIII could be replaced in the abovereaction scheme in a known manner with suitable cyclic moietiescorrespondingly generally to X as defined in the above formula (1) suchthat instead of the 4-benzylpiperidone of formula IX, a moiety isobtained having the generalized structure

-   -   in which X has the definition given above:

An alternate method disclosed in Commonly assigned U.S. Ser. No.09/575,060 could involve isonipecotoyl chlorides such as X which can beused to acylate appropriately substituted benzenes (ArH) in the presenceof a Lewis acid such as aluminum chloride to give the ketones XI, Scheme5. Further modifications of the carbonyl moiety of XI using methods androutes generally known can then lead to the desired compounds XII. Inthe present invention the cyclic precursor in compound X above can bereplaced with cyclic moieties corresponding generally to the monocyclicor polycyclic aliphatic moieties defined as “X” in the above formula(1).

Moreover, in the same manner that substituted piperazines XIII can bereacted with various and appropriate ArL²X in the presence or absence ofa base or other catalytic reagent to give the substituted piperazinesXV, Scheme 6, as described in commonly assigned U.S. Ser. No.09/575,060; compounds comprising the moiety “X” in formula (1) above canalso be reacted with ArL²X in a known manner to obtain analogs ofcompound XV in which the cyclic portion thereof is replaced with X informula (1) above. Compounds XV having a chiral center can be furtherresolved to the chiral components with the use of a chiral resolvingagent such as tartaric acid to give either enantiomers of thesubstituted compounds XV.

Compounds III can be treated with halides, acid chlorides and otherelectrophiles (BX), Scheme 7, containing a variety of differentsubstituents, in the presence of a base such as sodium hydride, in avariety of different solvents, to give compounds of type XVI. These canthen be converted to the corresponding acids XVII by treatment withappropriate reagents such as an aqueous base. As disclosed in commonlyassigned U.S. Ser. No. 09/575,060, the acids may then be coupled tosubstituted amines IX, XII or XV using a coupling agent such as EDAC.HClin a variety of solvents including methylene chloride, dimethylformamide, to give compounds XVIII. In accordance with the presentinvention the piperazine/piperadine component of compound XVIII may bereplaced with a cyclic aliphatic moiety “X” as defined in formula (1)above.

Compounds XVIII, or the analog thereof in which thepiperazine/piperazine ring is replaced with “X” in formula (1) above canbe first treated with acid chlorides such as oxalyl chloride inmethylene chloride under anhydrous conditions followed by treatment witha variety of nucleophiles WH to give compounds of type XIX, Scheme 8.

Assays for p38 α Kinase Inhibition

For each of the assay procedures described below, the TNF-α productioncorrelates to the activity of p38-α kinase.

A. Human Whole Blood Assay for p38 Kinase Inhibition

Venous blood is collected from healthy male volunteers into aheparinized syringe and is used within 2 hours of collection. Testcompounds are dissolved in 100% DMSO and 1 μl aliquots of drugconcentrations ranging from 0 to 1 mM are dispensed into quadruplicatewells of a 24-well microtitre plate (Nunclon Delta SI, AppliedScientific, So. San Francisco, Calif.). Whole blood is added at a volumeof 1 ml/well and the mixture is incubated for 15 minutes with constantshaking (Titer Plate Shaker, Lab-Line Instruments, Inc., Melrose Park,Ill.) at a humidified atmosphere of 5% CO₂ at 37° C. Whole blood iscultured either undiluted or at a final dilution of 1:10 with RPMI 1640(Gibco 31800+NaHCO₃, Life Technologies, Rockville, Md. and Scios, Inc.,Sunnyvale, Calif.). At the end of the incubation period, 10 μl of LPS(E. coli 0111:B4, Sigma Chemical Co., St. Louis, Mo.) is added to eachwell to a final concentration of 1 or 0.1 μg/ml for undiluted or 1:10diluted whole blood, respectively. The incubation is continued for anadditional 2 hours. The reaction is stopped by placing the microtitreplates in an ice bath and plasma or cell-free supernates are collectedby centrifugation at 3000 rpm for 10 minutes at 4° C. The plasma samplesare stored at −80° C. until assayed for TNF-α levels by ELISA, followingthe directions supplied by Quantikine Human TNF-α assay kit (R&DSystems, Minneapolis, Minn.).

IC₅₀ values are calculated using the concentration of inhibitor thatcauses a 50% decrease as compared to a control.

B. Enriched Mononuclear Cell Assay for p38 Kinase Inhibition

The enriched mononuclear cell assay, the protocol of which is set forthbelow, begins with cryopreserved Human Peripheral Blood MononuclearCells (HPBMCs) (Clonetics Corp.) that are rinsed and resuspended in awarm mixture of cell growth media. The resuspended cells are thencounted and seeded at 1×10⁶ cells/well in a 24-well microtitre plate.The plates are then placed in an incubator for an hour to allow thecells to settle in each well.

After the cells have settled, the media is aspirated and new mediacontaining 100 ng/ml of the cytokine stimulatory factorLipopolysaccharide (LPS) and a test chemical compound is added to eachwell of the microtitre plate. Thus, each well contains HPBMCs, LPS and atest chemical compound. The cells are then incubated for 2 hours, andthe amount of the cytokine Tumor Necrosis Factor Alpha (TNF-α) ismeasured using an Enzyme Linked Immunoassay (ELISA). One such ELISA fordetecting the levels of TNF-α is commercially available from R&DSystems. The amount of TNF-α production by the HPBMCs in each well isthen compared to a control well to determine whether the chemicalcompound acts as an inhibitor of cytokine production.

LPS Induced Cytokine Synthesis in HPBMCs

-   -   Cryopreserved HPBMC (cat#CC-2702 Clonetics Corp)    -   LGM-3 media (cat#CC-3212 Clonetics Corp)    -   LPS stock 10 μg/ml (Cat. No. L 2630 serotype 0111:B4 Sigma)    -   Human TNF-α ELISA (R&D Systems)    -   DNase I (10 mg/ml stock)

Preparation of Cells.

-   -   LGM-3 media warmed to 37° C.    -   5 μl of DNase I stock added to 10 ml media.    -   Cells thawed rapidly and dispersed into above.    -   Centrifuge 200×g×10 min @ RT.    -   Pellet up in 10 ml sterile PBS.    -   Centrifuge 200×g×10 min @ RT.    -   Pellet resuspended in 10 ml LGM-3 then diluted to 50 ml with        LGM-3.    -   Perform cell count.    -   Adjust to 1×E06 cells/well.    -   Seed 1 ml/well of a 24 well plate.    -   Place plate in incubator to plate down for 1 hour.

Preparation of Incubation Media.

-   -   LGM-3 containing 100 ng/ml LPS (e.g. 50 ml media plus 0.5 ml LPS        stock)    -   Aliquot into 2 ml aliquots and add 1000× inhibitor dilutions.

Incubation

When cells have plated down aspirate media away and overlay with 1 mlrelevant incubation media. Return plate to incubator for 2 hours or 24hours. Remove supernatants after incubation to a labeled tube and eitherperform TNF (or other) ELISA immediately or freeze for later assay.

IC₅₀ values are calculated using the concentration of inhibitor thatcauses a 50% decrease as compared to a control.

Administration and Use

The compounds of the invention are useful among other indications intreating conditions associated with inflammation. Thus, the compounds offormula (1) or their pharmaceutically acceptable salts are used in themanufacture of a medicament for prophylactic or therapeutic treatment ofmammals, including humans, in respect of conditions characterized byexcessive production of cytokines and/or inappropriate or unregulatedcytokine activity on such cells as cardiomyocytes, cardiofibroblasts andmacrophages.

The compounds of the invention inhibit the production of cytokines suchas TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MAPK (or p38), CSBP, or SAPK-2. The activation of thisprotein has been shown to accompany exacerbation of the diseases inresponse to stress caused, for example, by treatment withlipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38activity, therefore, is predictive of the ability of a medicament toprovide a beneficial effect in treating diseases such as Alzheimer's,coronary artery disease, congestive heart failure, cardiomyopathy,myocarditis, vasculitis, restenosis, such as occurs following coronaryangioplasty, atherosclerosis, IBD, rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis and other arthriticconditions, multiple sclerosis, acute respiratory distress syndrome(ARDS), asthma, chronic obstructive pulmonary disease (COPD), silicosis,pulmonary sarcosis, sepsis, septic shock, endotoxic shock, Gram-negativesepsis, toxic shock syndrome, heart and brain failure (stroke) that arecharacterized by ischemia and reperfusion injury, surgical procedures,such as transplantation procedures and graft rejections, cardiopulmonarybypass, coronary artery bypass graft, CNS injuries, including open andclosed head trauma, inflammatory eye conditions such as conjunctivitisand uveitis, acute renal failure, glomerulonephritis, inflammatory boweldiseases, such as Crohn's disease or ulcerative colitis, graft vs. hostdisease, bone resorption diseases like osteoporosis, type II diabetes,pyresis, psoriasis, cachexia, viral diseases such as those caused byHIV, CMV, and Herpes, and cerebral malaria.

Within the last several years, p38 has been shown to comprise a group ofMAP kinases designated p38-α, p38-β, p38-γ and p38-δ. Jiang, Y., et al.,J Biol Chem (1996) 271:17920-17926 reported characterization of p38-β asa 372-amino acid protein closely related to p38-α. In comparing theactivity of p38-α with that of p38-β, the authors state that while bothare activated by proinflammatory cytokines and environmental stress,p38-β was preferentially activated by MAP kinase kinase-6 (MKK6) andpreferentially activated transcription factor 2, thus suggesting thatseparate mechanisms for action may be associated with these forms.

Kumar, S., et al., Biochem Biophys Res Comm (1997) 235:533-538 andStein, B., et al., J Biol Chem (1997) 272: 19509-19517 reported a secondisoform of p38-β, p38-β2, containing 364 amino acids with 73% identityto p38-α. All of these reports show evidence that p38-β is activated byproinflammatory cytokines and environmental stress, although the secondreported p38-β isoform, p38-β2, appears to be preferentially expressedin the CNS, heart and skeletal muscle compared to the more ubiquitoustissue expression of p38-α. Furthermore, activated transcriptionfactor-2 (ATF-2) was observed to be a better substrate for p38-β2 thanfor p38-α, thus suggesting that separate mechanisms of action may beassociated with these forms. The physiological role of p38-β1 has beencalled into question by the latter two reports since it cannot be foundin human tissue and does not exhibit appreciable kinase activity withthe substrates of p38-α.

The identification of p38-γ was reported by Li, Z., et al., BiochemBiophys Res Comm (1996) 228:334-340 and of p38-δ by Wang, X., et al., JBiol Chem (1997) 272:23668-23674 and by Kumar, S., et al., BiochemBiophys Res Comm (1997) 235:533-538. The data suggest that these two p38isoforms (γ and δ) represent a unique subset of the MAPK family based ontheir tissue expression patterns, substrate utilization, response todirect and indirect stimuli, and susceptibility to kinase inhibitors.

Various results with regard to response to drugs targeting the p38family as between p38-α and either the putative p38-β1 or p38-β2 or bothwere reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A., et al., Chem and Biol (1995) 5:321-328. An additionalpaper by Wang, Y., et al., J Biol Chem (1998) 273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38-β activity results inhypertrophy, whereas activation of p38-α activity leads to myocyteapoptosis. Thus, selective inhibition of p38-α activity as compared top38-β activity will be of benefit in treating conditions associated withcardiac failure. These conditions include congestive heart failure,cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvulardisease, conditions associated with cardiopulmonary bypass, coronaryartery bypass, grafts and vascular grafts. Further, to the extent thatthe α-isoform is toxic in other muscle cell types, α-selectiveinhibitors would be useful for conditions associated with cachexiaattributed to TNF or other conditions such as cancer, infection, orautoimmune disease.

Thus, the invention encompasses the use of compounds which selectivelyinhibit the activity of the p38-α isoform for treating conditionsassociated with activation of p38-α, in particular those associated withcardiac hypertrophy, ischemia or other environmental stress such asoxidation injury, hyperosmolarity or other agents or factors thatactivate p38-α kinase, or cardiac failure, for example, congestive heartfailure, cardiomyopathy and myocarditis.

The manner of administration and formulation of the compounds useful inthe invention and their related compounds will depend on the nature ofthe condition, the severity of the condition, the particular subject tobe treated, and the judgment of the practitioner; formulation willdepend on mode of administration. As the compounds of the invention aresmall molecules, they are conveniently administered by oraladministration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

The compounds useful in the invention may also be administered throughsuppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

The compounds may also be administered topically, for topical conditionssuch as psoriasis, or in formulation intended to penetrate the skin.These include lotions, creams, ointments and the like which can beformulated by known methods.

The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

Alternative formulations include nasal sprays, liposomal formulations,slow-release formulations, and the like, as are known in the art.

Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

The dosages of the compounds of the invention will depend on a number offactors which will vary from patient to patient. However, it is believedthat generally, the daily oral dosage will utilize 0.001-100 mg/kg totalbody weight, preferably from 0.01-50 mg/kg and more preferably about0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending onthe conditions being treated and the judgment of the practitioner.

It should be noted that the compounds of formula (1) can be administeredas individual active ingredients, or as mixtures of several embodimentsof this formula. In addition, the inhibitors of p38 kinase can be usedas single therapeutic agents or in combination with other therapeuticagents. Drugs that could be usefully combined with these compoundsinclude natural or synthetic corticosteroids, particularly prednisoneand its derivatives, monoclonal antibodies targeting cells of the immunesystem, antibodies or soluble receptors or receptor fusion proteinstargeting immune or non-immune cytokines, and small molecule inhibitorsof cell division, protein synthesis, or mRNA transcription ortranslation, or inhibitors of immune cell differentiation or activation.

As implied above, although the compounds of the invention may be used inhumans, they are also available for veterinary use in treating animalsubjects.

The following examples are intended to illustrate but not to limit theinvention. The compounds prepared below are inhibitors of p38.

EXAMPLE 1 6-Chloro-3-dimethylaminooxalyl-1-methyl-1H-indole-5-carboxylicacid (1-benzyl-pyrrolidin-3 S-ylmethyl)-amide

The above compound was prepared using the following reaction scheme:

Step A

Synthesis of 2. To a solution of indole acid 1 (75 mg, 0.358 mMol) inDMF (1.5 mL) was added HATU (143 mg, 0.376 mMol) and triethylamine (92mg, 0.716 mMol). After shaking occasionally for 15 min, this solutionwas added to (3R)-1-benzyl-3-(aminomethyl)pyrrolidine (82 mg, 0.430mMol) and stirred overnight. The reaction was diluted with ethyl acetateand washed with water (×2) and brine. The organic layer was dried(Na₂SO₄), concentrated and chromatographed via radial chromatography(1:1 ETOAc:hexanes) to give 117 mg of a white solid.

Step B

Synthesis of Example 1 compound. A solution of Indole 2 (117 mg, 0.306mMol) in DCM (4 mL) was cooled to 0° C. and a 2.0 M solution of oxalylchloride (0.31 mL) in DCM was added dropwise via syringe. The reactionwas stirred at 0° C. for one hour and then allowed to warm to roomtemperature for one hour. The solvent was removed under vacuum. Thesolvent was replaced by DCM (4 mL) cooled to 0° C. and a 2.0 M solutionof dimethyl amine (0.62 mL) in DCM was added via syringe. After 0.5 hthe solution was warmed to room temperature and stirred for anadditional 30 minutes. The solvent was removed and the yellow residuere-suspended in DCM. The solution was washed with water, brine, dried(Na₂SO₄) and concentrated to give a yellow oil which was purified viaradial chromatography (3:97 methanol:chloroform) to give 47 mg of awhite solid.

EXAMPLE 2 6-Chloro-3-dimethylaminooxalyl-1-methyl-1H-indole-5-carboxylicacid (1-benzyl-pyrrolidin-3R-ylmethyl)-amide

The above compound was prepared using the same procedure used in Example1 using (3S)-1-benzyl-3-(aminomethyl)pyrrolidine in place of(3R)-1-benzyl-3-(aminomethyl)pyrrolidine.

EXAMPLE 32-{6-Chloro-5-[1-(4-fluoro-benzyl)-1,7-diaza-spiro[4.4]nonane-7-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide

Step A

Triethylamine (7.88 g, 77.9 mMol) was added to a stirred solution ofproline methyl ester (5.93 g, 35.4 mMol) in DCM (70 mL). The mixture wascooled to 0° C. and 4-fluorobenzoyl chloride (6.18 g, 39.0 mMol) wasadded slowly via syringe. The mixture was stirred for an additional 2 hrat 0° C. and allowed to warm to room temperature for an additional 2 h.The solution was then transferred to a separatory funnel, washed with10% citric acid, 5% potassium carbonate, brine, dried (Na₂SO₄) andconcentrated to give a thick oil. The residue was purified by flashchromatography to give 5.90 g of the product as a colorless oil.Step B

Tetraethylenediamine (3.09 g, 26.6 mMol) was added to a solution oflithium diisopropyl amide (2.61 g, 24.4 mMol) in THF (25 mL) at −78° C.After the solution was allowed to stir for 15 min, a solution of1-chloroacetonitrile (2.51 g, 33.3 mL) in THF (6 mL) was added dropwisevia addition funnel. The reaction was stirred for an additional 1 h at−78° C., warmed to 0° C. and stirred for an additional 30 min. Thereaction was then concentrated for form a dark oil, partitioned betweenDCM-water and the solid was removed by filtration. The organic layer wasseparated, washed with 2.0 M HCl, brine, dried (Na₂SO₄) and concentratedto give a dark oil. The residue was chromatographed using flashchromatography (30:70 EtOAc:hexanes) to give 3.34 g of the desiredproduct as a thick colorless oil.Step C

A solution of the nitrile (1.70 g, 5.82 mMol) was taken up in EtOH (50mL). Using a 2 mL scoop, two scoops of Raney nickel in water was added.The reaction was placed on a Parr shaker at 45 PSI H₂ for 5 days withadditional scoops of Raney nickel added on day 2 and 3. After 5 daysLCMS indicated near complete reduction of the nitrile to primary amine.The solution was filtered through celite and concentrated to giveslightly yellow oil. The oil was taken up in toluene (25 mL) andrefluxed for 48 hours. After removing the solvent, the resulting oil waschromatographed via radial chromatography to give 640 mg of the productas a white solid. Material was used without further purification.Step D

A solution of lithium aluminum hydride (2.3 mL, 2.29 mMol) in ether wasadded to a solution of the diamide in THF (20 mL). The reaction washeated to reflux overnight. An additional 2.3 mL of lithium aluminumhydride solution was added and again the reaction was allowed to refluxovernight. At this point solid lithium aluminum hydride (174 mg, 2.58mMol) was added and the reaction was refluxed for an addition 4 hours.The reaction was cooled to 0° C. and 0.35 mL water was added. When thebubbling died down 0.35 mL 15% sodium hydroxide was added followed by1.05 mL water and 5 g Na₂SO₄. The mixture was stirred for 1 h, filteredthrough celite and the solvent was removed to give a yellow oil thatcontains the crude product which was used without further purification.Step E

Synthesis of2-{6-Chloro-5-[1-(4-fluoro-benzyl)-1,7-diaza-spiro[4.4]nonane-7-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamidewas accomplished as described above for6-Chloro-3-dimethylaminooxalyl-1-methyl-1H-indole-5-carboxylic acid(1-benzyl-pyrrolidin-3 S-ylmethyl)-amide using1-(4-Fluoro-benzyl)-1,7-diaza-spiro[4.4]nonane in place of(3R)-1-benzyl-3-(aminomethyl)pyrrolidine.

EXAMPLE 42-{6-Chloro-5-[5-(4-fluoro-benzyl)-3a,6a-dimethyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide

Step A

To a suspension of p-toluenesulfonamide (27.5 g, 1660 mMol) andanhydrous K₂CO₃ (45 g) in anhydrous acetonitrile (250 ml) was added3-chloro-2-(chloromethyl)-1-propene (20 g, 160 mMol) in acetonitrile (25mL) dropwise. The reaction mixture was refluxed for 4 h, and thenconcentrated. The residue was extracted with hot ethyl acetate (3×). Thecombined extracts were concentrated and the crude solid wasre-crystallized from ethyl acetate to give 21 g (60%) of the titlecompound 1 as a colorless crystalline.Step B

A slurry ofN,N′-bis(p-toluenesulfonyl)-3,7-bis(methylene)-1,5-diazaacyclooctane(6.6 g, 9.9 mMol), LiAlH₄ (5.7 g, 150 mMol) in THF (200 mL) was stirredunder N₂ for 2 days. The reaction mixture was quenched with 20% NaOH (15mL) with external cooling and stirred continuously for 3 h. Theprecipitate was filtered off and washed with anhydrous ether. Thecombined extracts were concentrated to give 1.1 g of crude productcontaining some unidentified by-product. This product was used in thenext reaction without further purification.Step C

A mixture of the crude diamine (570 mg), 4-fluorobenzyl chloride (145mg, 1 mMol) in EtOH was heated at reflux for 3 h. The reaction mixturewas concentrated with Na₂CO₃ and extracted with EtOAc. The residue waspurified by chromatography on silica gel eluting with 5% MeOH in CH₂Cl₂.(MeOH was increase to 100% gradually) to give 75 mg of the product as awhite solid.Step D

To a solution of indole (95 mg, 0.45 mMol) and amine 3 (75 mg, 0.3 mMol)in DMF was added HATU (172 mg, 0.45 mMol), followed bydiisopropylethylamine (78 mg, 0.6 mMol). The reaction mixture wasstirred at RT overnight, then concentrated. The residue was treated withNa₂CO₃, and extracted with EtOAc. The organic extracts was dried andconcentrated. The residue was purified by chromatography on silica geleluting with hexane:EtOAc (3:2) to give 50 mg (38%) of compound 6 as awhite solid.Step E

Oxalyl chloride (0.1 mL, 0.2 mMol) was added to a solution of indole inCH₂Cl₂ (5 mL) at 0° C. The reaction mixture was warmed to rt. slowly,stirred for 5 h, concentrated and then dried for 2 h. The residue wasredissolved in CH₂Cl₂ and quenched with dimethylamine (0.2 mL, 0.4 mMol,2 M in THF). The reaction mixture was treated with Na₂CO₃ and extractedwith EtOAc. The combined extracts was dried and concentrated. Theresidue was purified on preparative TLC plate developed with 1% MeOH inEtOAc to give 2 mg of the desired product and 35 mg of the recoveredstarting material.

EXAMPLE 5 6-Chloro-3-dimethylaminooxalyl-1H-indole-5-carboxylic Acid{2-[(4-fluoro-benzyl)-methyl-amino]-cyclohexyl}-amide

Step A

To 4-fluorobenzaldehyde (2.48 g) in MeOH was added methylamine (40%aqueous solution, 2.0 mL). The reaction mixture was stirred at RT for 12h at which time NaBH₄ (0.38 g) was added. After stirring for 1 h thereaction was quenched with H₂O and extracted with ethyl acetate. Thecombined extracts were dried, filtered, and concentrated to yield(4-fluorobenzyl)-methylamine (2.30 g) which was used without furtherpurification.Step B

(4-Fluoro-benzyl)-methyl-(2-nitro-cyclohexyl)-amine was prepared bydissolving (4-fluorobenzyl)-methylamine (139 mg) in CH₂Cl₂ (2.25 mL) andtreating it with 1-nitro-1-cyclohexane (127 mg) at −78° C. and slowlywarming it to RT. After the reaction was complete as monitored by HPLC,the reaction mixture was concentrated to yield the desired product whichwas immediately in the next step.Step C

To crude (4-fluoro-benzyl)-methyl-(2-nitro-cyclohexyl)-amine (1.0 mMol)in (5:1) MeOH/H₂O (30 mL) was added Raney-Nickel. The reaction mixturewas placed under H₂ (1 atm) and stirred for 16 h. The slurry wasfiltered through Celite and the volatiles removed in vacuo to yieldN-(4-Fluoro-benzyl)-N-methyl-cyclohexane-1,2-diamine (20 mg).Step D

6-Chloro-3-dimethylaminooxalyl-1H-indole-5-carboxylic acid{2-[(4-fluoro-benzyl)-methyl-amino]-cyclohexyl}-amide was prepared asfor Example 1.

EXAMPLE 62-{5-[1-(4-Fluoro-benzyl)-piperidine-4-carbonyl]-6-methoxy-1-methyl-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide

Step A

Isonipecotic acid (5.37 g, 44.2 mMol) was dissolved at −10° C. in CH₂Cl₂under an atmosphere of argon. Et₃N (6.53 ml, 46.4 mMol) was slowlyadded, followed by trifluoroacetic anhydride (6.62 ml, 46.4 mMol). Thereaction mixture was stirred for 1 h at room temperature and then pouredinto H₂O. The organic phase was separated and evaporated to dryness. Thecrude material thus obtained was dissolved in Et₂O and extracted into a10% NaHCO₃ solution. Acidification to pH 4 with concentrated HCl andextraction with CH₂Cl₂ yielded, after evaporation, a white solid. (6.27g, 27.85 mMol, 63% yield)Step B

Acetic anhydride (10 ml) was added to a solution of m-anisidine (10 g)in 10 ml of acetic acid at 0° C. The solution was stirred overnight atroom temperature and then poured into 50 g of ice and 50 ml of water.The light pink solid was filtered and air-dried, yielding 10.5 g of theproduct.Step C

1.69 g (7.52 mMol) of amide was treated with 10 ml thionyl chloride at0° C. followed by heating the reaction mixture at reflux temperatureovernight. At the end of reaction, excess thionyl chloride was removedunder reduced pressure to give 1.83 g of the acid chloride. 1.37 g of3-methoxy-acetanilide (8.3 mMol) in 20 ml of dry CH₂Cl₂ was then addedto the above acid chloride, followed by slowly addition of 2.51 g (18.8mMol) aluminum chloride at ambient temperature. The reaction mixture washeated to reflux for 12 h. It was then cooled and poured into a mixtureof conc. HCl and ice. Product was extracted with EtOAc and the organiclayer was washed with water, half saturated sodium bicarbonate solutionand concentrated. Silica gel column separation (CH₂Cl₂) gave 0.42 g(1.13 mMol) of the product.Step D

0.417 g ofN-{3-Methoxy-4-[1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonyl]-phenyl}-acetamide(1.12 mMol) was dissolved in 5 ml of dry DMF followed by addition of0.12 g sodium periodate (0.56 mMol), 0.284 g iodine (1.12 mMol). Underargon protection, the reaction mixture was warmed up to 50° C. with anoil bath and continued for 24 hours. DMF was removed in vacuo, residuewas taken up in EtOAc and washed with H₂O, brine, dried over anhydroussodium sulfate and concentrated. Silica gel column separation (20% EtOAcin Hexane) afforded 0.33 g of product.Step E

To a dry and N₂ filled 25 ml RB flask is added 0.5 g ofN-{2-Iodo-5-methoxy-4-[1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonyl]-phenyl}-acetamide(1 mMol), 5 ml dry CH₂Cl₂, and 5 ml dry Et₃N. At 0° C., 0.11 mltrimethylsilylacetylene (1.1 mMol) is added dropwise. At the end ofaddition, the reaction mixture is warmed up to room temperature andstirred for 2 h. Solvent is evaporated off, residue which is thendissolved in EtOAc filtered through Celite. The combined filtrate iswashed with brine, dried over anhydrous sodium sulfate and concentrated.Silica gel column separation (40% EtOAc in Hexane) provide 0.42 g ofproduct.Step F

0.42 g ofN-{5-Methoxy-4-[1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonyl]-2-trimethylsilanyl-ethynyl-phenyl}-acetamide(0.9 mMol) is dissolved in 5 ml dry THF. Under nitrogen protection, 1.8ml tetrabutylammnonium fluoride (1.8 mMol, 1M in THF) is added. Themixture is then heated under reflux temperature for 1 h. After THF isremoved, residue is dried under vacuum, re-dissolved in EtOAc, washedwith H₂O, brine, dried over anhydrous sodium sulfate, and concentrated.Silical gel column separation (20% EtOAc in hexane) affords 0.22 gproduct.Step G

Under nitrogen protection, 177 mg of2,2,2-Trifluoro-1-[4-(6-methoxy-1H-indole-5-carbonyl)-piperidin-1-yl]-ethanone(0.5 mMol) is dissolved in 10 ml dry DMF. To this solution is added 22mg of NaH (0.55 mMol, 60% dispersion in mineral oil) at 0° C. Afterstirring at 0° C. for about 10 min, the reaction mixture is warmed up toroom temperature with continued stirring for 0.5 h. The reaction mixtureis cooled back to 0° C., followed by addition of 0.034 mL of methyliodide (0.55 mMol). The reaction is allowed to stir at 0° C. for 0.5 hbefore being warmed up to room temperature and with continued stirringat room temperature for 1 h. DMF is removed under reduced pressure,residue is taken up in CH₂Cl₂, washed with H₂O, brine, dried overanhydrous sodium sulfate and concentrated. Silica gel column separation(CH₂Cl₂) affords 177 mg of product.Step H

Under argon protection, 0.36 ml oxalyl chloride (0.72 mMol, 2M inCH₂Cl₂) is added into a 15-ml dry RB flask containing 177 mg of2,2,2-Trifluoro-1-[4-(6-methoxy-1-methyl-1H-indole-5-carbonyl)-piperidin-1-yl]-ethanone(0.48 mMol) in 2 ml dry CH₂Cl₂ at 0° C. The reaction mixture is stirredat 0° C. for 10 min before being warmed up to room temperature andstirred at room temperature for 1 hour. Excess of oxalyl chloride isremoved under vacuo and vacuum dried for 0.5 h. At 0° C., residue isdissolved in 2 ml dry CH₂Cl₂, followed by addition of 0.48 mL ofdimethylamine (0.96 mMol, 2 M in THF). The reaction mixture is thenstirred at 0° C. for 0.5 h before being warmed up to room temperatureand stirring continued for 1 h. At the end of reaction, solvent isremoved as well as unreacted dimethylamine residue. Residue isre-dissolved in CH₂Cl₂, washed with H₂O, brine, dried over anhydroussodium sulfate and concentrated. Silica gel column separation (2% MeOHin CHCl₃) gave 204 mg of product.Step I

To a 4 ml MeOH solution of 204 mg of2-{6-Methoxy-1-methyl-5-[1-(2,2,2-trifluoro-acetyl)-piperidine-4-carbonyl]-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide(0.44° C.mMol) is added 123 mg of KOH (2.2 mMol) in 4 ml H₂O. Thereaction mixture is heated at reflux temperature for 1 h before beingcooled down to room temperature. MeOH is removed in vacuo and 6 mL H₂Ois introduced to dilute the solution. Aqueous solution was thenextracted with CH₂Cl₂ and organic layer is washed with brine, dried overanhydrous sodium sulfate and concentrated to give 145 mg of product.Step J

144 mg of2-[6-Methoxy-1-methyl-5-(piperidine-4-carbonyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide(0.39 mMol) is dissolved in 10 ml EtOH followed by the addition of 0.05ml of 4-fluorobenzyl bromide (0.4 mMol). The reaction mixture is stirredat room temperature over night. After removing the solvent, residue istaken up in CH₂Cl₂ and washed with H₂O, brine, dried over anhydroussodium sulfate and concentrated. Silica gel column separation (2% MeOHin CH₂Cl₂) then gives 133 mg of product.

Additional Examples

Synthesis of 2: Methyl 4-amino-2-chlorobenzoate (1) (18.5 g) wasdissolved in dichloromethane (350 ml) and methyl thioacetaldehydedimethylacetal (13.6 g) was added. The mixture was cooled to −45° C.(dry ice/acetonitrile bath). N-chlorosuccinamide (16.0 g) in 350 mldichloromethane was added dropwise over 1 hr 30 min while maintainingbath temp at −45° C. The reaction mixture was stirred additional 1 hr,then triethylamine (16 mL, 100 mMols) in 30 ml dichloromethane was addeddropwise over 5 min, reaction was warmed to room temp, then refluxed for16 h. Solvent was removed and residue taken up in 500 ml carbontetrachloride, triethylamine-hydrochloric acid was removed byfiltration, filtrate was heated to reflux for 2 h. Solvent was removedby rotary evaporation.

The residue was dissolved in 250 ml tetrahydrofuran and 250 ml 10%hydrochloric acid was added. The mixture was stirred overnight at roomtemperature until the complete disappearance of the starting materialwas observed. Solvent was removed under vacuum, acidic aqueous solutionwas extracted with ethyl acetate (3×125 ml). The combined ethyl acetateextracts were washed with 10% hydrochloric acid, water and dried overanhydrous sodium sulfate. Solvent was removed under vacuum. Crudeproduct mixture was purified on a silica column eluting with ethylacetate:hexanes (15:85) to give 6.4 g of the desired product 2.

Synthesis of 3: Methyl 6-Chloro-3-thiomethyl-5-indole carboxylate (5.2g) was dissolved in 150 ml ethanol:tetrahydrofuran (9:3) and treatedwith Raney-Nickel. Reaction was monitored by mass spec at 30 minintervals, with subsequent addition of Raney-Nickel until reaction wascomplete. When reaction was complete reaction was carefully filteredthrough celite and the celite washed with methanol several times andfiltrate evaporated. Residue was taken up in ethyl acetate, washed withwater, dried over anhydrous sodium sulfate. The solvent was removed togive 3 (3.2 g).

Synthesis of 4: Methyl ester 1.5 g was dissolved in 30 ml methanol/water50:50. The reaction mixture was heated at 50° C. for 2 h with 4 Mol.equivalent sodium hydroxide. The reaction mixture was cooled inice-bath, acidified to pH 3 with 5M hydrochloric acid. Removed methanolby rotary evaporation and extracted with ethyl acetate. The extract waswashed with saturated sodium chloride and dried over anhydrous sodiumsulfate. Evaporation of the solvent gave the desired acid 4 (1.48 g).

Synthesis of 15: To a solution of aniline 1 (9.25 g, 0.05 mol) andpyruvic aldehyde dimethyl acetal 14 (11.8 g, 0.1 mol) in 200 mL glacialacetic acid was added anhydrous sodium sulfate (71.0 g, 0.5 mol) and themixture was stirred for 30 min. Powdered sodium triacetoxy borohydride(31.8 g, 0.15 mol) was then added in portions for a period of 5 min. Thereaction mixture was stirred for an additional 2 h. Acetic acid wasremoved under reduced pressure and the residue was made basic by addingsufficient amount of saturated sodium bicarbonate solution. The productwas then extracted with ethyl acetate, dried with sodium sulfate andevaporated to get an oil. This was chromatographed on silica gel columnusing ethyl acetate:hexane (3:7) to give 15 (14 g) as colorless oil.

Synthesis of 16 and 17: To a suspension of fresh aluminum chloride (18.5g) in 200 ml dry chloroform at 0° C. was added a solution of ketal 15(13.3 g) in 100 ml chloroform slowly and the mixture was allowed to warmup to the room temperature and stirred overnight. Ice-cold water wasadded carefully to quench the aluminum chloride and the organic layerwas separated and washed with sodium bicarbonate solution, dried andevaporated to get a white solid. The isomers were separated using silicagel column chromatography using ethyl acetate:hexane (1:9). The 6-choloindole 17 (2.0 g) eluted first followed by 4-chloro isomer 16 (3.8 g).

Synthesis of 18. To a solution of 1.3 g of indole 17 in 15 mL ofmethanol was added a solution of 0.9 g of sodium hydroxide in 20 mL ofwater. The reaction mixture was heated at 50° C. for 4 h where upon aclear solution resulted. Cooled and evaporated off methanol and theresidue was diluted with water and acidified with 10% hydrochloric acid.The product was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and evaporated to obtain indole acid18 (1.2 g) as white solid.

2-Methyl-6-methoxyindole-5-carboxylic acid was also synthesized usingthe above synthetic procedure.

Synthesis of 21: To a solution of methyl 4-amino-6-methoxy 5-benzoate(19) (6.0 g, 0.033 mol) and dimethyl acetal 20 (7.0 g, 0.066 mol) in 150mL glacial acetic acid was added anhydrous sodium sulfate (47.0 g, 0.33mol) and the mixture was stirred for 30 min. Powdered sodium triacetoxyborohydride (20.1 g, 0.099 mol) was then added in portions for a periodof 5 min. The reaction mixture was stirred for an additional 2 h. Aceticacid was removed under reduced pressure and the residue was made basicby adding sufficient amount of saturated sodium bicarbonate solution.The product was then extracted with ethyl acetate, washed with saturatedsodium chloride, dried over sodium sulfate and evaporated to get an oil.This was chromatographed on silica gel column using ethyl acetate:hexane(3:7) as eluent and the desired product 21 was obtained (5.2 g) as anoil.

Synthesis of 22: To a solution of 21 (3.6 g) and iodomethane (5.7 g) in50 mL anhydrous dimethylformamide was added potassium t-butoxide (1.0 Min tetrahydrofuran, 20 mL) at ambient temperature. The reaction mixturewas stirred at ambient temperature for 0.5 h and poured into 250 mLethyl acetate, washed with water (4×100 mL), brine (50 mL) and driedover magnesium sulfate. Evaporation of solvent afforded 3.26 g of 22.The product was used for next step without purification.

Synthesis of 23: To a suspension of anhydrous aluminum chloride (0.71 g)in 20 mL anhydrous 1,2-dichloroethane was added, dropwise a solution of22 (1 g) in 10 mL 1,2-dichloroethane with stirring. The reaction washeated to 80° C. for 0.5 h. At the end of this time, the reactionmixture was quenched with methanol, solvents evaporated, then ethylacetate (100 mL) was added. The organic phase was washed with water, aq.sodium bicarbonate and brine and concentrated. The crude product waspurified by silica chromatography using ethyl acetate:hexane (3:7) togive 23 0.22 g.

1. A compound of the formula:

and the pharmaceutically acceptable salts thereof wherein: Ar is an arylgroup substituted with 0-5 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl,heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl,NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR,OCONR₂, RCO, COOR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, andNO₂, wherein each R is independently H, alkyl, alkenyl or aryl orheteroforms thereof and wherein two of said optional substituents onadjacent positions can be joined to form a fused, optionally substitutedaromatic or nonaromatic, saturated or unsaturated ring which contains3-8 members; X is an aliphatic monocyclic or aliphatic polycyclic moietyoptionally comprising one or more hetero ring atoms wherein the cyclicmoiety may be optionally substituted with one or more noninterferingsubstituents and where said optional substituents may constitute a ringfused to X; L¹ is CO, SO₂, alkylene (1-4C), or CH₂NHCO; L² is alkylene(1-4C) or alkenylene (2-4C) optionally substituted with one or twomoieties selected from the group consisting of alkyl, alkenyl, alkynyl,aryl, arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR₂, SR,SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOCR,SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, and R₃Si, wherein each R isindependently H, alkyl, alkenyl or aryl or heteroforms thereof andwherein two substituents on L² can be joined to form a non-aromaticsaturated or unsaturated ring that includes 0-3 heteroatoms which are O,S and/or N and which contains 3 to 8 members or said two substituentscan be joined to form a carbonyl moiety or an oxime, oximeether,oximeester or ketal of said carbonyl moiety; with the proviso that —X—is not:

wherein Z^(a) is CR or N wherein R is hydrogen or a noninterferingsubstituent; each R^(a) is independently a noninterfering substituent;and each of 1 and k is 0-3; and m is 0-4; n is 0-3; each R¹ isindependently halo, alkyl, OCOR, OR, NRCOR, SR, or NR₂, wherein R ishydrogen, alkyl or aryl or heteroforms thereof;

represents a single or double bond; one Z² is CA or CR²A; the other Z²is CR³, CR³ ₂, NR⁴ or N; and each R², R³ and R⁴ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroalkyl, heteroalkenyl, heteroalkynyl,heteroalkylaryl, heteroaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R,OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, SO₃R, CONR₂, SO₂NR₂,NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H,alkyl, alkenyl or aryl or heteroforms thereof and two of R² and/or R³ onadjacent positions can be joined to form a fused, optionally substitutedaromatic or nonaromatic, saturated or unsaturated ring which contains3-8 members, or an oxime, oximeether, oximeester or ketal thereof; Z³ isNR⁵ or O; where R⁵ is H or is optionally substituted alkyl, alkenyl,alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl,heteroalkenyl, heteroalkynyl, heteroalkylaryl, or is SOR, SO₂R, RCO,COOR, alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, NR₂, OR, alkyl-SR,alkyl-SOR, alkyl-SO₂R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR₂, orR₃Si, wherein each R is independently H, alkyl, alkenyl or aryl orheteroforms thereof; A is -W_(i)-COX_(j)Y, where Y is selected fromCOR⁶, tetrazole, 1,2,3-triazole, 1,2,4-triazole, and imidazole, each ofW and X is substituted or unsubstituted alkylene or alkenylene, each of2-6 Å; each of i and j is independently 0 or 1; and R⁶ is H, or isstraight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substitutedwith halo, alkyl, SR, SOR, SO₂R, SO₂NR₂, OR, NR₂, OCOR, NRCOR, NRCONR₂,NRSO₂R, NRSO₂NR₂, OCONR₂, CN, COOR, CONR₂, COR, or R₃Si wherein each Ris independently H, alkyl, alkenyl or aryl or heteroforms thereof, orwherein R⁶ is OR, NR₂, SR, NRCONR₂, OCONR₂, or NRSO₂NR₂, wherein each Ris independently H, alkyl, alkenyl or aryl or heteroforms thereof andwherein two R attached to the same atom may form a 3-8 membercarbocyclic or heterocyclic ring and wherein said ring may further besubstituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, each optionally substituted with halo, SR,OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, or R₃Si whereineach R is independently H, alkyl, alkenyl or aryl or heteroforms thereofwherein two R attached to the same atom may form a 3-8 member ring,optionally substituted as above defined.
 2. The compound of claim 1wherein Y is COR⁶.
 3. The compound of claim 2 wherein Y is tetrazole;1,2,3-triazole; 1,2,4-triazole; or imidazole.
 4. The compound of claim 1wherein each of i and j is
 0. 5. The compound of claim 1 wherein j is 0.6. The compound of claim 1 wherein Z³ is NR⁵.
 7. The compound of claim 1wherein R⁵ is H, or is optionally substituted alkyl or acyl.
 8. Thecompound of claim 1 wherein R² and R³ are independently selected fromhalo, OR and alkyl.
 9. The compound of claim 1 wherein L¹ is CH₂ or COand L² is CH₂ or CHOH.
 10. The compound of claim 9 wherein L¹ is CO. 11.The compound of claim 1 wherein L² and/or L¹ is unsubstituted alkylene.12. The compound of claim 1 wherein L² and/or L¹ is unsubstitutedmethylene, or methylene substituted with alkyl.
 13. The compound ofclaim 1 wherein Ar is optionally substituted phenyl.
 14. The compound ofclaim 13 wherein said optional substitution is by halo, OR, or alkyl.15. The compound of claim 14 wherein said phenyl is unsubstituted or hasa single substituent.
 16. The compound of claim 1 wherein R¹ is halo oralkoxy.
 17. The compound of claim 16 wherein n is 0, 1 or
 2. 18. Thecompound of claim 1 wherein L¹ is coupled to the α ring at the 4-, 5- or6-position.
 19. The compound of claim 1 wherein Z² at position 3 is CAor CHA.
 20. The compound of claim 19 wherein the Z² at position 2 is CR³or CR³ ₂.
 21. The compound of claim 20 wherein R³ is hydrogen, or isselected from the group consisting of alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroaryl, NH-aroyl, halo, OR, NR₂, SR, SOR,SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, SO₃R, CONR₂,SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R isindependently H, alkyl, alkenyl or aryl and two of R¹ can be joined toform a fused, optionally substituted aromatic or nonaromatic, saturatedor unsaturated ring which contains 3-8 members.
 22. The compound ofclaim 21 wherein each R³ is selected from the group consisting of H,alkyl, acyl, aryl, arylalkyl, heteroaryl, halo, OR, NR₂, SR, NRCOR, RCO,COOR, and CN, wherein each R is independently H, alkyl or aryl.
 23. Thecompound of claim 19 wherein Z² at position 2 is N or NR⁴.
 24. Thecompound of claim 23 wherein R⁴ is H, or alkyl, alkenyl, alkynyl, aryl,arylalkyl, acyl, aroyl, heteroaryl, or is SOR, SO₂R, RCO, COOR,alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, or R₃Si wherein each R isindependently H, alkyl, alkenyl or aryl.
 25. The compound of claim 1wherein

represents a double bond.
 26. The compound of claim 1 wherein theportion of the compound represented by L²-X-L¹ is selected from thegroup consisting of:

wherein, in each of structures (I) to (IV): one or more of the ringcarbon atoms not bound to L² or L¹ may be optionally replaced with NR⁴,where R⁴ is as defined in claim 1; or is represented by CR² ₂, where R²is as defined in claim 1 but at least one R² is other than H; and/or oneor both of the ring carbon atoms bound to L² and L¹ may be independentlyreplaced by CR² where R² is as defined in claim 1, but is other than H;and/or one or both of the ring carbon atoms bound to L² and L¹ may bereplaced by N.
 27. The compound of claim 26 wherein R² and R³ areindependently selected from halo, OR and alkyl.
 28. The compound ofclaim 26 wherein L²-X-L¹ is structure II and n and p are both 1, or nand p are both 2, or one of n and p is 1 and the other is
 2. 29. Thecompound of claim 26 wherein L²-X-L¹ is structure (IV) and n and p areboth
 2. 30. The compound of claim 26 wherein the ring carbon bonded toL¹ is replaced with N; or the ring carbon bonded to L² is replaced withN; or both of said ring carbons are replaced with N.
 31. The compound ofclaim 26 wherein the ring carbon bonded to L² is replaced with nitrogenand the ring atom bonded to L¹ is carbon.
 32. The compound of claim 26wherein L² is methylene and -L¹- is —CH₂—NH—CO— such that the portion ofthe compound represented by L²-X-L¹- consists of CH₂—X—CH₂—NH—CO—. 33.The compound of claim 26 wherein L²-X-L¹ is selected from:


34. The compound of claim 26 wherein the compound is:


35. A pharmaceutical composition which composition comprises atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable excipient.
 36. A method to treat rheumatoidarthritis, which comprises administering to a subject in need of suchtreatment a compound of claim 1 or a pharmaceutical composition thereof.